Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/06—Tripeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/07—Tetrapeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
  • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06104—Dipeptides with the first amino acid being acidic
  • C07K5/06113—Asp- or Asn-amino acid

Definitions

• the invention described herein pertains to drug delivery conjugates for targeted therapy.
• the invention described herein relates to methods of treating PSMA expressing cancers with a PSMA ligand-tubulysin compound.
• the invention described herein also relates to methods of treating PSMA-expressing cancers with a PSMA ligand-tubulysin compound in patients where stable disease results after treatment with the PSMA ligand-tubulysin compound.
• Prostate specific membrane antigen is a type II cell surface membrane-bound glycoprotein with -110 kD molecular weight, including an intracellular segment (amino acids 1-18), a transmembrane domain (amino acids 19-43), and an extensive extracellular domain (amino acids 44-750). While the functions of the intracellular segment and the transmembrane domains are currently believed to be insignificant, the extracellular domain is involved in several distinct activities. PSMA plays a role in the central nervous system, where it metabolizes N-acetyl-aspartyl glutamate (NAAG) into glutamic and N-acetyl aspartic acid.
• NAAG N-acetyl-aspartyl glutamate
• PSMA is also sometimes referred to as an N-acetyl alpha linked acidic dipeptidase (NAALADase).
• PSMA is also sometimes referred to as a folate hydrolase I (FOLH I) or glutamate carboxypeptidase (GCP II) due to its role in the proximal small intestine where it removes ⁇ -linked glutamate from poly-y-glutamated folate and a-linked glutamate from peptides and small molecules.
• FOLH I folate hydrolase I
• GCP II glutamate carboxypeptidase
• PSMA is named largely due to its higher level of expression on prostate cancer cells; however, its particular function on prostate cancer cells remains unresolved.
• PSMA is over- expressed in the malignant prostate tissues when compared to other organs in the human body such as kidney, proximal small intestine, and salivary glands. Unlike many other membrane- bound proteins, PSMA undergoes rapid internalization into the cell in a similar fashion to cell surface bound receptors like vitamin receptors. PSMA is internalized through clathrin-coated pits and subsequently can either recycle to the cell surface or go to lysosomes. It has been suggested that the dimer and monomer form of PSMA are inter-convertible, though direct evidence of the interconversion is being debated. Even so, only the dimer of PSMA possesses enzymatic activity, and the monomer does not.
• PSMA represents a viable target for the selective and/or specific delivery of biologically active agents, including drug compounds and imaging agents to such prostate cells.
• biologically active agents including drug compounds and imaging agents to such prostate cells.
• One such drug compound is tubulysin, which when conjugated to PSMA through an appropriately functionalized linker provides
• Imaging agent is the PSMA ligand-imaging conjugate of formula Ilia
• Imaging conjugate Ilia has found use as a cancer imaging agent as described in, for example, WO2009/026177.
• the present disclosure provides a method for treating a cancer in a patient in need of such treatment comprising, administering to the patient a therapeutically effective amount of a PSMA ligand-tubulysin compound I
• the present disclosure provides use of a PSMA ligand-tubulysin compound I
• the use comprises administering to the patient a therapeutically effective amount of the PSMA ligand-tubulysin compound I, or a pharmaceutically acceptable salt thereof.
• the present disclosure provides use of a PSMA ligand-tubulysin compound I
• the medicament comprises a therapeutically effective amount of the PSMA ligand-tubulysin compound I, or a pharmaceutically acceptable salt thereof.
• the cancer is a PSMA expressing cancer. In some aspects of these embodiments, the compound is at least about 98 percent pure. In some embodiments, the cancer is selected from the group consisting of a glioma, a carcinoma, a sarcoma, a lymphoma, a melanoma, a mesothelioma, a nasopharyngeal carcinoma, a leukemia, an adenocarcinoma, and a myeloma.
• the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, metastatic breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non- small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphomas, pleural mesothelioma, cancer
• the cancer is a primary or secondary brain cancer. In some aspects of these embodiments, the cancer is prostate cancer. In some aspects of these embodiments, the cancer is metastatic prostate cancer. In some aspects of these embodiments, the PSMA ligand-tubulysin compound I, or a pharmaceutically acceptable salt thereof, is administered in a parenteral dosage form. In some aspects of these embodiments, the parenteral dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal. In some aspects of these embodiments, the therapeutically effective amount is from about 0.1 mg/m 2 to about 6.0 mg/m 2.
• the therapeutically effective amount is from about 0.1 mg/m 2 to about 5.0 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from about 0.1 mg/m 2 to about 4.0 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from about 0.1 mg/m 2 to about 3.5 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from about 0.1 mg/m 2 to about 3.0 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from about 0.1 mg/m 2 to about 2.5 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from about 0.1 mg/m to about 2.0 mg/m 2 .
• the therapeutically effective amount is from 0.1 mg/m 2 to 6.0 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from 0.1 mg/m 2 to 5.0 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from 0.1 mg/m 2 to 4.0 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from 0.1 mg/m 2 to 3.5 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from 0.1 mg/m to 3.0 mg/m . In some aspects of these embodiments, the therapeutically effective amount is from 0.1 mg/m 2 to 2.5 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from 0.1 mg/m 2 to 2.0 mg/m 2.
• the methods and uses described herein further comprise imaging PSMA expression by the cancer.
• the step of imaging occurs before the step of administering.
• the imaging is performed by imaging wherein the imaging is selected from the group consisting of SPECT imaging, PET imaging, IHC, and FISH.
• the imaging is performed by SPECT imaging.
• the step of imaging comprises administering to the patient a PSMA ligand-imaging conjugate of the formula II or a pharmaceutically acceptable salt thereof, wherein R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein a radionuclide is bound to the conjugate.
• the step of imaging comprises administering a PSMA li and-imaging conjugate of the formula III
• M in the conjugate, or a pharmaceutically acceptable salt thereof is selected from the group consisting of an isotope of gallium, an isotope of indium, an isotope of copper, an isotope of technetium, and an isotope of rhenium. In some aspects of these embodiments, M in the conjugate, or a pharmaceutically acceptable salt thereof, is an isotope of technetium.
• the PSMA ligand-imaging conjugate is of the formula Ila or a pharmaceutically acceptable salt thereof, wherein a radionuclide is bound to the conjugate. In some aspects of these embodiments, the PSMA ligand-imaging conjugate is of the formula Ilia
• the methods and uses described herein further comprise determining the PSMA status of the patient by imaging.
• the imaging is SPECT imaging.
• the PSMA status of the patient correlates with a clinical benefit to the patient.
• the clinical benefit is selected from the group consisting of inhibition of tumor growth, stable disease, a partial response, and a complete response.
• the clinical benefit is stable disease.
• the PSMA positive lesions indicate functionally active PSMA.
• the step of determining comprises administering to the patient a PSMA ligand-imaging conjugate of the formula II
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein the conjugate is bound to a radionuclide.
• the step of determining comprises administering a PSMA li and-imaging conjugate of the formula III
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein M is a cation of a radionuclide.
• M in the conjugate, or a pharmaceutically acceptable salt thereof is selected from the group consisting of an isotope of gallium, an isotope of indium, an isotope of copper, an isotope of technetium, and an isotope of rhenium. In some aspects of these embodiments, M in the conjugate, or a pharmaceutically acceptable salt thereof, is an isotope of technetium. In some aspects of these embodiments, the PSMA ligand- imaging conjugate is of the formula Ila
• the PSMA ligand-imaging conjugate is of the formula Ilia
• the present disclosure provides a method of treating a cancer in a patient in need of such treatment comprising, administering to the patient a therapeutically effective amount of a PSMA ligand-tubulysin compound I
• the present disclosure provides use of a PSMA ligand-tubulysin compound I
• the use comprises administering to the patient a therapeutically effective amount of the PSMA ligand-tubulysin compound I.
• the present disclosure provides use of a PSMA ligand-tubulysin compound I
• the medicament comprises a therapeutically effective amount of the PSMA ligand- tubulysin compound I, or a pharmaceutically acceptable salt thereof.
• the patient has been treated with at least one prior treatment.
• the at least one prior treatment is selected from the group consisting of a chemotherapeutic agent, surgery, radiation therapy, immunotherapy, photodynamic therapy, stem cell therapy, and hyperthermia.
• the at least one prior treatment is a systemic treatment.
• the systemic treatment is selected from the group consisting of palifosfamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafinib, and combinations thereof.
• the cancer is a PSMA expressing cancer.
• the compound is at least about 98 percent pure.
• the cancer is selected from the group consisting of a glioma, a carcinoma, a sarcoma, a lymphoma, a melanoma, a mesothelioma, a
• the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, metastatic breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non-small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the pen
• the cancer is a primary or secondary brain cancer.
• the cancer is prostate cancer.
• the cancer is metastatic prostate cancer.
• the PSMA ligand-tubulysin compound I, or a pharmaceutically acceptable salt thereof is administered in a parenteral dosage form.
• the parenteral dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.
• the parenteral dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.
• the therapeutically effective amount is from about 0.1 mg/m to about 6.0 mg/m . In some aspects of these embodiments, the therapeutically effective amount is
• therapeutically effective amount is from about 0.1 mg/m to about 4.0 mg/m . In some aspects of these embodiments, the therapeutically effective amount is from about 0.1 mg/m to about 3.5 mg/m . In some aspects of these embodiments, the therapeutically effective amount is from
• effective amount is from about 0.1 mg/m to about 2.5 mg/m . In some aspects of these
• the therapeutically effective amount is from about 0.1 mg/m to about 2.0 mg/m .
• the therapeutically effective amount is from 0.1
• the amount is from 0.1 mg/m to 5.0 mg/m . In some aspects of these embodiments, the
• therapeutically effective amount is from 0.1 mg/m to 4.0 mg/m . In some aspects of these
• the therapeutically effective amount is from 0.1 mg/m to 3.5 mg/m . In some aspects of these embodiments, the therapeutically effective amount is from 0.1 mg/m to 3.0 mg/m . In some aspects of these embodiments, the therapeutically effective amount is from 0.1
• the methods and uses described herein further comprise imaging PSMA expression by the cancer.
• the step of imaging occurs before the step of administering.
• the imaging is performed by imaging wherein the imaging is selected from the group consisting of SPECT imaging, PET imaging, IHC, and FISH.
• the imaging is performed by SPECT imaging.
• the step of imaging comprises administering to the patient a PSMA ligand-imaging conjugate of the formula II
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein a radionuclide is bound to the conjugate.
• the step of imaging comprises administering a PSMA li and-imaging conjugate of the formula III
• M in the conjugate, or a pharmaceutically acceptable salt thereof is selected from the group consisting of an isotope of gallium, an isotope of indium, an isotope of copper, an isotope of technetium, and an isotope of rhenium. In some aspects of these embodiments, M in the conjugate, or a pharmaceutically acceptable salt thereof, is an isotope of technetium.
• the PSMA ligand-imaging conjugate is of the formula Ila
• the PSMA ligand-imaging conjugate is of the formula Ilia
• the methods and uses described herein further comprise determining the PSMA status of the patient by imaging.
• the imaging is SPECT imaging.
• the PSMA status of the patient correlates with a clinical benefit to the patient.
• the clinical benefit is selected from the group consisting of inhibition of tumor growth, stable disease, a partial response, and a complete response.
• the clinical benefit is stable disease.
• the step of determining comprises administering to the patient a PSMA ligand-imaging conjugate of the formula II or a pharmaceutically acceptable salt thereof, wherein R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein a radionuclide is bound to the conjugate.
• the step of determining comprises administering a PSMA li and-imaging conjugate of the formula III
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherin M is a cation of a radionuclide.
• M in the conjugate, or a pharmaceutically acceptable salt thereof is selected from the group consisting of an isotope of gallium, an isotope of indium, an isotope of copper, an isotope of technetium, and an isotope of rhenium. In some aspects of these embodiments, M in the conjugate, or a pharmaceutically acceptable salt thereof, is an isotope of technetium. In some aspects of these embodiments, the PSMA ligand- imaging conjugate is of the formula Ila or a pharmaceutically acceptable salt thereof, wherein a radionuclide is bound to the conjugate.
• the PSMA ligand-imaging conjugate is of the formula Ilia
• the present disclosure provides a method of treating a PSMA expressing cancer in a patient in need of such treatment comprising, administering to the patient a therapeutically effective amount of a PSMA ligand-tubulysin compound I
• the present disclosure provides use of a PSMA ligand-tubulysin compound I
• the use comprises administering to the patient a therapeutically effective amount of a PSMA ligand-tubulysin compound I, or a pharmaceutically acceptable salt thereof.
• the present disclosure provides use of a PSMA ligand-tubulysin compound I
• the medicament comprises a therapeutically effective amount of the PSMA ligand- tubulysin compound I, or a pharmaceutically acceptable salt thereof.
• the patient has been treated with at least one prior treatment.
• the at least one prior treatment is selected from the group consisting of a chemotherapeutic agent, surgery, radiation therapy, immunotherapy, photodynamic therapy, stem cell therapy, and hyperthermia.
• the at least one prior treatment is a systemic treatment.
• the systemic treatment is selected from the group consisting of palifosfamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafinib, and combinations thereof.
• the cancer is a PSMA expressing cancer.
• the compound is at least about 98 percent pure.
• the cancer is selected from the group consisting of a glioma, a carcinoma, a sarcoma, a lymphoma, a melanoma, a mesothelioma, a
• the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, metastatic breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non-small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the pen
• the cancer is a primary or secondary brain cancer.
• the cancer is prostate cancer.
• the cancer is metastatic prostate cancer.
• the PSMA ligand-tubulysin compound I, or a pharmaceutically acceptable salt thereof is administered in a parenteral dosage form.
• the parenteral dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.
• the therapeutically effective amount is from about 0.1 mg/m to about 6.0 mg/m . In some aspects of these embodiments, the therapeutically effective amount is
• therapeutically effective amount is from about 0.1 mg/m to about 4.0 mg/m . In some aspects of these embodiments, the therapeutically effective amount is from about 0.1 mg/m to about 3.5 mg/m . In some aspects of these embodiments, the therapeutically effective amount is from
• the therapeutically effective amount is from about 0.1 mg/m 2 to about 2.5 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from about 0.1 mg/m 2 to about 2.0 mg/m 2.
• the therapeutically effective amount is from 0.1 mg/m 2 to 6.0 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from 0.1 mg/m 2 to 5.0 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from 0.1 mg/m 2 to 4.0 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from 0.1 mg/m 2 to 3.5 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from 0.1 mg/m to 3.0 mg/m . In some aspects of these embodiments, the therapeutically effective amount is from 0.1 mg/m 2 to 2.5 mg/m 2. In some aspects of these embodiments, the therapeutically effective amount is from 0.1 mg/m 2 to 2.0 mg/m 2.
• the methods described herein further comprise imaging PSMA expression by the cancer.
• the step of imaging occurs before the step of administering.
• the imaging is performed by imaging and the imaging is selected from the group consisting of SPECT imaging, PET imaging, IHC, and FISH.
• the imaging is performed by SPECT imaging.
• the step of imaging comprises administering to the patient a PSMA ligand-imaging conjugate of the formula II
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein a radionuclide is bound to the conjugate.
• the step of imaging comprises administering a PSMA ligand-imaging conjugate of the formula III or a pharmaceutically acceptable salt thereof, wherein R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein M is a cation of a radionuclide.
• M in the conjugate, or a pharmaceutically acceptable salt thereof is selected from the group consisting of an isotope of gallium, an isotope of indium, an isotope of copper, an isotope of technetium, and an isotope of rhenium. In some aspects of these embodiments, M in the conjugate, or a pharmaceutically acceptable salt thereof, is an isotope of technetium.
• the PSMA ligand-imaging conjugate is of the formula Ila
• the PSMA ligand-imaging conjugate is of the formula Ilia
• the methods described herein further comprise determining the PSMA status of the patient by imaging.
• the imaging is SPECT imaging.
• the PSMA status of the patient correlates with a clinical benefit to the patient.
• the clinical benefit is selected from the group consisting of inhibition of tumor growth, stable disease, a partial response, and a complete response.
• the clinical benefit is stable disease.
• the step of determining comprises administering to the patient a PSMA ligand-imaging conjugate of the formula II
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein a radionuclide is bound to the conjugate.
• the step of determining comprises administering a PSMA ligand-imaging conjugate of the formula III
• M in the conjugate, or a pharmaceutically acceptable salt thereof is selected from the group consisting of an isotope of gallium, an isotope of indium, an isotope of copper, an isotope of technetium, and an isotope of rhenium.
• M in the conjugate, or a pharmaceutically acceptable salt thereof is an isotope of technetium.
• the PSMA ligand- imaging conjugate is of the formula Ila
• the PSMA ligand-imaging conjugate is of the formula Ilia
• a method for treating a cancer in a patient in need of such treatment comprising, administering to the patient a therapeutically effective amount of a PSMA ligand-tubulysin compound I
• the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, metastatic breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non- small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphomas, pleural mes
• parenteral dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein a radionuclide is bound to the conjugate.
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein M is a cation of a radionuclide.
• step of determining comprises administering to the patient a PSMA ligand-imaging conjugate of the formula II
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein a radionuclide is bound to the conjugate.
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein M is a cation of a radionuclide.
• M in the conjugate, or a pharmaceutically acceptable salt thereof is selected from the group consisting of an isotope of gallium, an isotope of indium, an isotope of copper, an isotope of technetium, and an isotope of rhenium.
• a method of treating a cancer in a patient in need of such treatment comprising, administering to the patient a therapeutically effective amount of a PSMA ligand-tubulysin compound I
• systemic treatment is selected from the group consisting of palifosfamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafinib, and combinations thereof.
• the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, metastatic breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non-small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphomas, pleural
• parenteral dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein a radionuclide is bound to the conjugate.
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein M is a cation of a radionuclide.
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein a radionuclide is bound to a conjugate.
• step of determining comprises administering a PSMA ligand-imaging conjugate of the formula III or a pharmaceutically acceptable salt thereof, wherein R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherin M is a cation of a radionuclide.
• a method of treating a PSMA expressing cancer in a patient in need of such treatment comprising, administering to the patient a therapeutically effective amount of a PSMA ligand-tubulysin compound I
• the present disclosure provides use of a PSMA ligand- tubulysin compound I
• Fig. 1A shows a PET bone scan of a tumor lesion
• Fig. IB shows a PSMA-imaging conjugate Ilia ( 99m Tc-EC0652) scan of the tumor lesion shown in Fig. 1A.
• PSMA-imaging conjugate Ilia 99m Tc-EC0652 showed good uptake in the tumor lesion.
• PSMA functionally active PSMA
• PSMA ligands are well known to those skilled in the art such as those described in US patent publication no. US 2010/0324008 Al, incorporated herein by reference.
• clinical benefit means a response of a patient to treatment with PSMA ligand-tubulysin compound I where the response includes overall survival of the patient, ability to receive four or more cycles of therapy (e.g., four weeks of therapy) with PSMA ligand-tubulysin compound I, inhibition of tumor growth, stable disease, a partial response, and/or a complete response, among other clinical benefits defined by the Food and Drug Administration in the United States of America.
• inhibiting tumor growth means reduction in tumor size, complete disappearance of a tumor, or growth of a patient tumor of less than 30% over the course of therapy with PSMA ligand-tubulysin compound I.
• stable disease means no material progression of disease in a patient over the course of therapy with PSMA ligand-tubulysin compound I.
• a partial response means a decrease in tumor size of 30% or greater in a patient treated with PSMA ligand-tubulysin compound I.
• a complete response means the disappearance of detectable disease in a patient treated with PSMA ligand-tubulysin compound I.
• prior treatment means the patient has been treated with at least one prior treatment known in the art. It will be appreciated that a prior treatment can be any treatment known to those of skill in the art, including, but not limited,
• Prior treatments can include systemic treatments including, but not limited to treatment with palifosf amide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafinib, and combinations thereof.
• alkyl includes a chain of carbon atoms, which is optionally branched. It will be further understood that in certain embodiments, alkyl is advantageously of limited length, including Ci-C 24 , Ci-Ci 2 , Ci-C 8 , Ci-C 6 , and Ci-C 4 .
• such particularly limited length alkyl groups including Ci-C 8 , Ci-C 6 , and Ci-C 4 may be referred to as lower alkyl. It is appreciated herein that shorter alkyl, alkenyl, and/or alkynyl groups may add less lipophilicity to the compound and accordingly will have different pharmacokinetic behavior. In embodiments of the invention described herein, it is to be understood, in each case, that the recitation of alkyl refers to alkyl as defined herein, and optionally lower alkyl.
• Illustrative alkyl groups include, but not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like.
• a "carboxyalkyl” group includes a
• a "alkyl” group as described herein with a “carboxy” group includes a combination of an “alkyl” group as described herein with a “carboxy” group.
• a “hydroxyalkyl” group includes a combination of an “alkyl” group as described herein with a “hydroxy” group.
• a “aminoalkyl” group includes a combination of an “alkyl” group as described herein with a “amino” group.
• heteroalkyl includes a chain of atoms that includes both carbon and at least one heteroatom, and is optionally branched.
• Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also include phosphorus, and selenium.
• aryl includes monocyclic and polycyclic aromatic carbocyclic groups having from 6 to 14 ring carbon atoms, each of which may be optionally substituted.
• Illustrative aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like.
• heteroaryl includes aromatic heterocyclic groups, having from 5 to 10 ring atoms, each of which may be optionally substituted.
• Illustrative aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl,
• heteroarylalkyl includes a combination of an “alkyl” group as described herein with a
• arylalkyl includes a combination of an "alkyl” group as described herein with a “aryl” group described herein, for example a benzyl group.
• optionally substituted includes the replacement of hydrogen atoms with other functional groups on the radical that is optionally substituted.
• Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like.
• any of amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.
• the term "administering" as used herein includes all means of introducing the PSMA ligand-tubulysin compound and PSMA ligand-imaging conjugates described herein to the patient, including, but not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like.
• the PSMA ligand-tubulysin compound and PSMA ligand-imaging conjugates described herein may be administered in unit dosage forms and/or formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and vehicles.
• a "patient” can be administered the PSMA ligand- tubulysin compound or PSMA ligand-imaging conjugates described herein, and can be human or, in the case of veterinary applications, can be a laboratory, agricultural, domestic, or wild animal.
• the patient can be a human, a laboratory animal such as a rodent (e.g.
• mice, rats, hamsters, etc. mice, rats, hamsters, etc.
• a rabbit, a monkey, a chimpanzee domestic animals such as dogs, cats, and rabbits
• agricultural animals such as cows, horses, pigs, sheep, goats, and wild animals in captivity such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins, and whales.
• the cancers described herein can be a cancer cell population that is tumorigenic, including benign tumors and malignant tumors, or the cancer can be non- tumorigenic.
• the cancer can arise spontaneously or by such processes as mutations present in the germline of the patient or somatic mutations, or the cancer can be chemically-, virally-, or radiation-induced.
• Cancers applicable to the invention described herein include, but are not limited to, a glioma, a carcinoma, a sarcoma, a lymphoma, a melanoma, a mesothelioma, a nasopharyngeal carcinoma, a leukemia, an adenocarcinoma, and a myeloma.
• the cancers can be lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, metastatic breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non-small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphomas, pleural mesothelioma, cancer of the bladder, Burkitt's lymph
• PSMA ligand-imaging conjugates detectable by PET imaging, SPECT imaging, and the like can be used.
• the exact manner of imaging is not limited to the imaging agents described herein.
• PSMA ligand-imaging conjugates useful for imaging described herein, including those described by formulas and the agents useful for PET imaging, SPECT imaging, etc. are referred to as "PSMA ligand-imaging conjugates.”
• the PSMA ligand-tubulysin compound and PSMA ligand-imaging conjugates described herein bind to expressed PSMA on cancer cells.
• the PSMA ligand-tubulysin compound and PSMA ligand-imaging conjugates are capable of differentially binding to PSMA on cancer cells compared to normal cells due to preferential expression (or over-expression) of PSMA on the cancer cells.
• pharmaceutically acceptable salts of the PSMA ligand-tubulysin compound and PSMA ligand-imaging conjugates described herein are provided.
• Pharmaceutically acceptable salts of the PSMA ligand-tubulysin compound and PSMA ligand-imaging conjugates described herein include acid addition and base salts thereof.
• Suitable acid addition salts are formed from acids which form non-toxic salts.
• Illustrative examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tos
• Suitable base salts of the PSMA ligand-tubulysin compound and PSMA ligand-imaging conjugates described herein are formed from bases which form non-toxic salts.
• bases which form non-toxic salts.
• Illustrative examples include the arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
• Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
• the PSMA ligand-tubulysin compound and PSMA ligand-imaging conjugates described herein may be administered as a formulation in association with one or more pharmaceutically acceptable carriers.
• the carriers can be excipients.
• the choice of carrier will to a large extent depend on factors such as the particular mode of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form.
• Pharmaceutical compositions suitable for the delivery of PSMA ligand-tubulysin compound and PSMA ligand-imaging conjugates described herein and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington: The Science & Practice of Pharmacy, 21th Edition (Lippincott Williams & Wilkins, 2005), incorporated herein by reference.
• a pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, and combinations thereof, that are physiologically compatible.
• the carrier is suitable for parenteral administration.
• Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Supplementary active compounds can also be incorporated into compositions of the invention.
• liquid formulations may include suspensions and solutions.
• Such formulations may comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and/or suspending agents.
• Liquid formulations may also be prepared by the reconstitution of a solid.
• an aqueous suspension may contain the active materials in admixture with appropriate excipients.
• excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally-occurring phosphatide, for example, lecithin; a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol; a condensation product of ethylene oxide with a partial ester derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate; or a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example,
• dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Additional excipients, for example, coloring agents, may also be present.
• Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth; naturally-occurring phosphatides, for example, soybean lecithin; and esters including partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
• isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride can be included in the composition.
• Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
• Illustrative formats for oral administration include tablets, capsules, elixirs, syrups, and the like.
• the route of administration and/or whether the PSMA ligand-tubulysin compound and/or PSMA ligand-imaging conjugates are administered locally or systemically a wide range of permissible dosages are contemplated herein, including doses falling in the range from about 1 ⁇ g/kg to about 1 g/kg.
• the dosages may be single or divided, and may administered according to a wide variety of protocols, including q.d., b.i.d., t.i.d., or even every other day, biweekly (b.i.w.), once a week, once a month, once a quarter, and the like.
• the therapeutically effective amounts described herein correspond to the instance of administration, or alternatively to the total daily, weekly, monthly, or quarterly dose, as determined by the dosing protocol.
• a PSMA ligand-tubulysin compound or a PSMA ligand-imaging conjugate as described herein may be administered directly into the blood stream, into muscle, or into an internal organ.
• Suitable routes for such parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, epidural, intracerebroventricular, intraurethral, intrasternal, intracranial, intratumoral, intramuscular and subcutaneous delivery.
• Suitable means for parenteral administration include needle (including microneedle) injectors, needle- free injectors and infusion techniques.
• parenteral formulations are typically aqueous solutions which may contain carriers or excipients such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
• a suitable vehicle such as sterile, pyrogen-free water.
• any of the liquid formulations described herein may be adapted for parenteral administration of the PSMA ligand-tubulysin compound or PSMA ligand-imaging conjugates described herein.
• parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
• solubility of a PSMA ligand-tubulysin compound or a PSMA ligand-imaging conjugate used in the preparation of a parenteral formulation may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
• formulations for parenteral administration may be formulated for immediate and/or modified release.
• active agents of the invention i.e., the PSMA ligand-tubulysin compound or PSMA ligand-imaging conjugates
• the active PSMA ligand-tubulysin compound or PSMA ligand-imaging conjugates can be prepared with carriers that will protect the PSMA ligand-tubulysin compound or PSMA ligand-imaging conjugate against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
• Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PGLA). Methods for the preparation of such formulations are generally known to those skilled in the art.
• the PSMA ligand-tubulysin compound or PSMA ligand-imaging conjugates described herein or compositions comprising the PSMA ligand-tubulysin compound or PSMA ligand-imaging conjugates may be continuously administered, where appropriate.
• kits are provided. If a combination of active PSMA ligand- tubulysin compound and PSMA ligand-imaging conjugates is to be administered, two or more pharmaceutical compositions may be combined in the form of a kit suitable for sequential administration or co-administration of the compositions.
• a kit comprises two or more separate pharmaceutical compositions, at least one of which contains a PSMA ligand-tubulysin compound or PSMA ligand-imaging conjugate described herein, and means for separately retaining the compositions, such as a container, divided bottle, or divided foil packet.
• compositions comprising one or more of the PSMA ligand-tubulysin compound or PSMA ligand-imaging conjugates described herein, in containers having labels that provide instructions for use of the PSMA ligand-tubulysin compound or PSMA ligand- imaging conjugates for patient selection and/or treatment are provided.
• sterile injectable solutions can be prepared by incorporating the active agent in the required amount in an appropriate solvent with one or a combination of ingredients described above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the active PSMA ligand-tubulysin compound or PSMA ligand-imaging conjugate into a sterile vehicle which contains a dispersion medium and any additional ingredients of those described above.
• the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof, or the ingredients may be sterile-filtered together.
• the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
• the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• PSMA ligand-tubulysin compound I can be administered as single doses, or the doses can be divided and administered as a multiple-dose daily regimen.
• a staggered regimen for example, one to five days per week can be used as an alternative to daily treatment, and for the purpose of the methods described herein, such intermittent or staggered daily regimen is considered to be equivalent to every day treatment and is contemplated.
• the patient is treated with multiple injections of PSMA ligand-tubulysin compound I to treat the cancer.
• the patient is injected multiple times (preferably about 2 up to about 50 times) with PSMA ligand-tubulysin compound I, for example, at 12-72 hour intervals or at 48-72 hour intervals. Additional injections of PSMA ligand-tubulysin compound I can be administered to the patient at an interval of days or months after the initial injections(s) and the additional injections can prevent recurrence of the cancer.
• PSMA ligand-tubulysin compound I is administered in a single daily dose administered five days a week, in weeks 1, 2, and 3 of each 4 week cycle, with no dose administered in week 4.
• PSMA ligand-tubulysin compound I is administered in a single daily dose administered three days a week, of weeks 1, and 3 of each 4 week cycle, with no dose administered in weeks 2 and 4.
• PSMA ligand-tubulysin compound I is administered biweekly on weeks 1 and 2, i.e. on days 1, 4, 8, 11, of a 3-week cycle.
• PSMA ligand-tubulysin compound I is administered once weekly on weeks 1 and 2, i.e. days 1 and 8 of a 3-week cycle.
• the unitary daily dosage of the PSMA ligand-tubulysin compound I can vary significantly depending on the patient condition, the cancer being treated, the route of administration of the PSMA ligand-tubulysin compound I and tissue distribution, and the possibility of co-usage of other therapeutic treatments, such as radiation therapy or additional drugs in combination therapies.
• the effective amount to be administered to a patient is based on body surface area, mass, and physician assessment of patient condition.
• Therapeutically effective doses (also referred to herein as "therapeutically effective amount”) can range, for example, from about 0.5 mg/m 2 to about 10.0 mg/m 2.
• the therapeutically effective doses described herein also include ranges of about 0.5 mg/m 2 to about 9.5 mg/m 2 , about 0.5 mg/m 2 to about 9.0 mg/m 2 , about 0.5 mg/m 2 to about 8.5 mg/m 2 , about 0.5 mg/m 2 to about 8.0 mg/m 2 , about 0.5 mg/m 2 to about 7.5 mg/m 2 , about 0.5 mg/m 2 to about 7.0 mg/m 2 , about 0.5 mg/m 2 to about 6.5 mg/m 2 , about 0.5 mg/m 2 to about 6.0 mg/m 2 , about 0.5 mg/m 2 to about 5.5 mg/m 2 , about 0.5 mg/m 2 to about 5.0 mg/m 2 , about 0.5 mg/m 2 to about 4.5 mg/m 2 , about 0.5 mg/m 2 to about 4.0 mg/m 2 , about 0.5 mg/m 2 to about 3.5 mg/m 2 , about 0.5 mg/m 2 to about 3.0 mg/m 2 , about
• the therapeutically effective dose may vary within the various ranges provided above based on the factors noted above.
• the therapeutically effective dose for any particular patient or group of patients may be any number value between about 0.5 mg/m 2 and about 10.0 mg/m 2 , including but not limited to 1.0 mg/m 2 , 1.5, mg/m 2 , 2.0 mg/m 2 , 2.5 mg/m 2 , 3.0 mg/m 2 , 3.5 mg/m 2 , 4.0 mg/m 2 , 4.5 mg/m 2 , 5.0 mg/m 2 , 5.5 mg/m 2 , 6.0 mg/m 2 , 6.5 mg/m 2 , 7.0 mg/m 2 , 7.5 mg/m 2 , 8.0 mg/m 2 , 8.5 mg/m 2 , 9.0 mg/m 2 ,
• the total dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
• the PSMA ligand-imaging conjugates and PSMA ligand-tubulysin compound described herein may contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. Accordingly, it is to be understood that the present invention includes pure stereoisomers as well as mixtures of stereoisomers, such as enantiomers, diastereomers, and enantiomerically or diastereomerically enriched mixtures.
• the PSMA ligand-imaging conjugates and PSMA ligand-tubulysin compound described herein may be capable of existing as geometric isomers. Accordingly, it is to be understood that the present invention includes pure geometric isomers or mixtures of geometric isomers.
• PSMA ligand-imaging conjugates and PSMA ligand-tubulysin compound described herein may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention.
• the PSMA ligand-imaging conjugates and PSMA ligand-tubulysin compound described herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
• compositions and/or dosage forms for administration of PSMA ligand-tubulysin compound I are prepared from PSMA ligand-tubulysin compound I with a purity of at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5%.
• compositions and or dosage forms for administration of PSMA ligand-tubulysin compound I are prepared from PSMA ligand- tubulysin compound I with a purity of at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%.
• compositions and/or dosage forms for administration of the PSMA ligand-imaging conjugate are prepared from the PSMA ligand-imaging conjugate with a purity of at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5%.
• compositions and or dosage forms for administration of the PSMA ligand-imaging conjugate are prepared from the PSMA ligand- imaging conjugate with a purity of at least 90%, or at least 95%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%.
• compositions and/or dosage forms for administration of radiolabeled PSMA ligand-imaging conjugate are prepared from the PSMA ligand-imaging conjugate with a radiochemical purity of at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5%.
• compositions and or dosage forms for administration of the PSMA ligand-imaging conjugate are prepared from the PSMA ligand-imaging conjugate with a purity of at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%.
• PSMA ligand-tubulysin compound I or the PSMA ligand-imaging conjugates described herein may be measured using any conventional technique, including various chromatography or spectroscopic techniques, such as high pressure or high performance liquid chromatography (HPLC), nuclear magnetic resonance spectroscopy, TLC, UV absorbance spectroscopy, fluorescence spectroscopy, and the like.
• HPLC high pressure or high performance liquid chromatography
• TLC nuclear magnetic resonance spectroscopy
• UV absorbance spectroscopy fluorescence spectroscopy
• the PSMA ligand-tubulysin compound or PSMA ligand- imaging conjugate described herein is provided in a sterile container or package.
• a clinical benefit of the patient to treatment with PSMA ligand-tubulysin compound I can be characterized utilizing Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
• the criteria have been adapted from the original WHO Handbook (3), taking into account the measurement of the longest diameter for all target lesions: complete response, (CR)— the disappearance of all target lesions; partial response (PR)— at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter; stable disease (SD)— neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started; progressive disease (PD)— at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.
• overall disease response rate is a clinical benefit and is calculated as the percent of patients who achieve a best response of CR or PR.
• Overall disease control rate (DCR) can be another clinical benefit and is calculated as the percent of patients who achieve a best response of CR, PR, or SD.
• overall survival is the time to death for a given patient defined as the number of days from the first day the patient received protocol treatment (C1D1) to the date of the patient's death. All events of death can be included, regardless of whether the event occurred while the patient was still taking the study drug or after the patient discontinued the study drug. If a patient has not died, then the data can be censored at the last study visit, or the last contact date, or the date the patient was last known to be alive, whichever is last.
• C1D1 patient received protocol treatment
• a clinical benefit of the patient as a result of treatment with PSMA ligand- tubulysin compound I can be characterized as inhibition of tumor growth which can be identified in a patient through, for example, follow-up imaging of the patient's cancer after treatment with PSMA ligand-tubulysin compound I.
• inhibition of tumor growth can be characterized by measuring the size of tumors in a patient after administration of PSMA ligand-tubulysin compound I according to any of the imaging techniques described herein, where the inhibition of tumor growth is indicated by a stable tumor size, or by a reduction in tumor size. It will be appreciated that the identification of inhibition of tumor growth can be accomplished using a variety of techniques, and is not limited to the imaging methods described herein (e.g CT, MRI, PET imaging, SPECT imaging or chest x-ray).
• a method is provided of determining whether PSMA ligand- tubulysin compound I is indicated for the treatment of a patient with cancer, the method comprising the step of determining the PSMA status in a patient with cancer wherein PSMA ligand-tubulysin compound I is indicated for the treatment of the patient if the PSMA status of the patient is positive.
• a method is provided of assessing whether PSMA ligand-tubulysin compound I is indicated for the treatment of a patient with one of the cancers described herein.
• the method comprises the steps of visually determining PSMA status in the patient wherein PSMA status is based on a imaging tumors that are PSMA positive in the patient, and wherein the PSMA ligand-tubulysin compound I is indicated for the treatment of the patient when the PSMA status of the patient is positive.
• a clinical benefit of PSMA ligand-tubulysin compound I treatment is indicated.
• the clinical benefit to the patient can be overall survival of the patient, ability to receive four or more cycles of therapy with PSMA ligand-tubulysin compound I, inhibition of tumor growth, stable disease, a partial response of the patient to therapy, a complete response of the patient to therapy, disease control (i.e., the best result obtained is a complete response, a partial response, or stable disease), and/or overall disease response (i.e., the best result obtained is a complete response or a partial response).
• the clinical benefit for a patient being treated for pleural mesothelioma or adenocarcinoma is stable disease.
• the methods described herein include the following examples.
• the examples further illustrate additional features of the various embodiments of the invention described herein.
• the examples are illustrative and are not to be construed as limiting other embodiments of the invention described herein.
• other variations of the examples are included in the various embodiments of the invention described herein.
• PSMA ligand-tubulysin compound I was prepared according to the methods described in United States Patent Publication No. WO2014/078484, incorporated herein by reference. Specifically, PSMA ligand-tubulysin compound I is prepared according to the following procedure. a. Synthesis of 3-
• TES protected dipeptide was dissolved in 100 mL THF (anhydrous, inhibitor- free), cooled to -45 °C, and stirred at -45 °C for 15 minutes before adding KHMDS (0.5 M in toluene, 61 mL, 1.05 equiv.), drop-wise. After the addition of KHMDS was finished, the reaction was stirred at -45 °C for 20 minutes, and chloromethyl butyrate (4.4 mL, 1.1 equiv.) was added. The reaction mixture was stirred at -45 °C for another 20 minutes. The reaction was quenched with 25 mL MeOH and warmed to room temperature.
• alkylated dipeptide 9 (26.97 mmol.), N-methyl pipecolinate (MEP) (5.51 g, 1.4 equiv.) and pentafluorophenol (7.63 g, 1.5 equiv.) were added to a 300 mL hydrogenation flask. NMP (115 mL) was then added, followed by EDC (7.78 g, 1.5 equiv.). The mixture was stirred at room temperature for overnight. 16.5 g of alkylated dipeptide 9 was dissolved in 16.5 mL NMP, transferred the solution into the hydrogenation flask, washed the residual 9 with 8 mL NMP, and transferred into the hydrogenation flask.
• Methyl ester 10 (6.9 g, 9.7 mmol) was dissolved in 1,2-dichloroethane (193 mL) and added to a round bottomed flask, equipped with a stir bar and condenser. To this solution was added trimethyltin hydroxide (24.6 g, 14 eq.). The mixture was heated at 70 °C for 5 hours. LC-MS analysis indicated that the desired product had been formed and ⁇ 15 % of starting methyl ester 10 remained. The reaction was cooled in an ice bath for 30 minutes. The resulting precipitate was then removed by filtration. The filtrate was stored overnight at -20 °C. The filtrate was then divided into two portions and each was subjected the chromatography procedure which follows.
• tripeptide acid 11 (3.9 g, 5.6 mmol) was dissolved in anhydrous THF (23 mL). To this solution was added 3 HF'TEA complex (1.8 mL, 2 eq.). The reaction was stirred at room temperature for 1 hour. LC-MS analysis indicated complete conversion to the desired des-TES product 12. The solvent was removed under reduced pressure and the residue was placed on the high vacuum for 40 minutes. The resulting residue was then dissolved in pyridine (26 mL), and acetic anhydride (7.9 mL, 15 eq.) and DMAP (25 mg) were added. The reaction was stirred at room temperature for 1 hour.
• H-Glu(OtBu)-OtBu HCl (101) (4.83g, 16.3 mmol, available from Sigma- Aldrich) and 4-nitrophenyl chloroformate (102) (3.47g, 17.2 mmol, available from Sigma- Aldrich) were dissolved in dichloromethane (50mL) and stirred in an ice bath under argon. Diisopropylethylamine (6.28mL, 36.1 mmol) was added slowly, dropwise and the reaction mixture was stirred in the ice bath for 5 min, then warmed to room temperature and stirred for 30 min.
• Boc-4-aminomethylphenylacetic acid (106) (2.00g, 7.5 mmol, available from VWR) dissolved in a solution of trifluoroacetic acid (9.75mL) and triisopropylsilane (0.25mL) and stirred at room temperature for 30 min, then concentrated under reduced pressure and coevaporated with dichloromethane (3x), then placed under vacuum, to yield 4- aminomethylphenylacetic acid (107) (quantitative yield).
• k Preparation of compound 108.
• H-Cys(4-methoxytrityl)-2-chlorotrityl-resin (0.87 mmol) was loaded and washed with isopropyl alcohol (3xl0mL) followed by dimethylformamide (3xl0mL). To the vessel was then introduced Fmoc-Asp(OtBu)-OH (2.0 equiv) in
• a peptide synthesis vessel 109 (0.18 mmol) was loaded and washed with isopropyl alcohol (3xl0mL) followed by dimethylformamide (3xl0mL). Fmoc deprotection was carried out using 20% piperidine in dimethylformamide (3x10 mL). Kaiser tests were performed to assess reaction completion. To the vessel was then introduced 108 (1.2 equiv) in
• Peptide was cleaved from the resin using a cleavage mixture consisting of dithiothreitol (114mg, 0.74 mmol) dissolved in a solution of trifluoroacetic acid (19mL), H 2 0 (0.5mL), triisopropylsilane (0.5mL).
• a cleavage mixture consisting of dithiothreitol (114mg, 0.74 mmol) dissolved in a solution of trifluoroacetic acid (19mL), H 2 0 (0.5mL), triisopropylsilane (0.5mL).
• One-third of the cleavage mixture was introduced and argon was bubbled for 30 min.
• the cleavage mixture was drained into a clean flask.
• the resin was bubbled 2 more times with more cleavage mixture, for 30 min each, and drained into a clean flask.
• PSMA imaging conjugate Ila was prepared according to the following scheme as taught in US patent publication number US20100324008 Al, which is incorporated herein by reference. Specifically, PSMA imaging conjugate Ila was prepared according to the following method.
• PSMA imaging conjugate Ila was synthesized using standard
• Fmoc fluorenylmethyloxycarbonyl
• SPPS solid phase peptide synthesis
• a 12 liter volume of Water For Injection (WFI) was sparged with nitrogen. Solutions of 1.0 M NaOH and 0.2 M HCI were prepared and sparged with nitrogen for pH adjustment of the formulation and for preparation of the stannous chloride stock solution. 2000 mL of deoxygenated WFI was added to a 5L jacketed formulation vessel which was connected to a chiller. The chiller solution was set at 5 °C and circulation was maintained throughout the compounding and filtration process. 88.6 g of sodium gluconate and 1063 mg of EDTA disodium dihydrate were weighed and transferred to the formulation vessel and dissolved. A stannous chloride stock solution at a concentration of lOmg/mL was made using the previously prepared 0.2 M HCI.
• a PSMA imaging conjugate Ila kit vial was removed from the refrigerator and allowed to warm to room temperature (17-27 °C) for 15-30 min.
• the vial was put into a suitable radioactive shielding container.
• One to Two milliliter ( ⁇ 50 mCi) of 99m Tc pertechnetate injection was added to the vial using a lead shielded syringe.
• equal volume of headspace was withdrawn in order to normalize the pressure inside the vial.
• the vial was gently swirled to completely dissolve the powder and then allowed to stand at ambient temperature (17-27 °C) for 15 minutes.
• 5-6 mL of 0.9% sodium chloride injection, USP was then added to the vial.
• the labeled solution was stored at room temperature (17-27 °C) and used within 6 hours of preparation.
• mCRPC metastatic, castration-resistant prostate cancer
• Prior dose escalation methodology for both schedules was based the continuous reassessment method (CRM), in which 1 patient is assigned to 1 dose level. Subsequent patients were to be enrolled upon the first observation of DLT, at which time enrollment to that dose level would be expanded to a maximum of 6 patients.
• An alternative dose escalation methodology for both schedules was based upon the standard "3+3" approach, in which a minimum of 3 patients is enrolled to a given dose level. Following the first observation of a DLT, the dose level is then expanded to a maximum of 6 patients.
• CCM continuous reassessment method
• ICF informed consent form
• Patients must be > 18 years of age. 3. Patients must have histological, pathological, and/or cytological confirmation of prostate cancer.
• mCRPC metastatic, castration-resistant prostate cancer
• Documented progressive metastatic CRPC will be based on at least one of the following criteria:
• PSA progression defined as 25% increase over baseline value with an increase in the absolute value of at least 2 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval and a minimum PSA of 2 ng/mL.
• Soft-tissue progression defined as an increase > 20% in the sum of the longest diameter (LD) of all target lesions based on the smallest sum LD since treatment started or the appearance of one or more new lesions.
• contraindication e.g. poor performance status, age or personal choice.
• Baseline and follow up radiological disease assessments must include bone scans performed with either Technetium-99m labeled diphosphonates or Fluorine- 18 sodium fluoride PET or PET/CT, as per the local standard of care for patients with prostate cancer.
• Bone marrow reserve Absolute neutrophil count (ANC) > 1.5 x 109/L. Platelets > 100 x 10 9 /L. Hemoglobin > 9 g/dL.
• LVEF Left ventricular ejection fraction
• ALT aminotransferase
• AST aspartate aminotransferase
• Renal Serum creatinine ⁇ 1.5 x ULN, or for patients with serum creatinine > 1.5 ULN, creatinine clearance > 50 mL/min.
• Any systemic anti-cancer therapy e.g., chemotherapy, immunotherapy or biological therapy [including monoclonal antibodies] within 28 days prior to beginning study therapy.
• PSMA Imaging Agent Ila labeled with 20-25 mCi of technetium- 99 TM (PSMA Imaging Agent Ilia). Patients were subjected to SPECT/CT imaging of the region(s) known to contain target lesion(s) approximately 3-4 hours after injection of PSMA Imaging Agent IIIa ( 99m Tc-EC0652). For sites where SPECT/CT imaging is not available, SPECT imaging alone was carried out.
• PSMA-Tubulysin Compound I PSMA ligand-tubulysin compound I was administered at least 4 days after PSMA Imaging Agent Ilia was administered, as an
• intravenous bolus injection ⁇ on Weeks 1 and 2 (i.e., on Days 1, 3, 5, 8, 10, 12 of a 3-week cycle) or once weekly on Weeks 1 and 2 of a 3 -week schedule.
• the starting dose of EC 1169 on Schedule 1 was 0.2 mg/m
• the table below outlines the dose levels for PSMA ligand-tubulysin compound I for Schedule #1 ⁇ dosing, with up to 14 doses levels of PSMA ligand-tubulysin compound I planned. Should the MTD not be determined after escalation of PSMA ligand-tubulysin compound I to dose level 6, PSMA ligand-tubulysin compound I may continue to be dose escalated in 25% increments.
• the starting dose of EC 1169 was 0.30 mg/m .
• the table below outlines the dose levels for PSMA ligand-tubulysin compound I for Schedule #2 TIW dosing, with up to 14 doses levels of PSMA ligand-tubulysin compound I planned. Should the MTD not be determined after escalation of PSMA ligand-tubulysin compound I to dose level 6, PSMA ligand-tubulysin compound I may continue to be dose escalated in 25% increments.
• DLTs will be based on events occurring in Part A during the first cycle of therapy and the adverse events must be drug related (i.e. definitely, probably or possibly):
• Grade 3 non-hematological toxicity • > Grade 3 non-hematological toxicity. Grade 3 laboratory abnormalities (e.g., K or Mg) that persist for less than 48 hours are not considered DLTs. • Grade 3 nausea, vomiting lasting more than 72 hours.
• Schedule #1 TIW Dosing Schedule: Inability to administer at least 4 of the 6 scheduled doses of PSMA ligand-tubulysin compound I in a cycle due to drug-related toxicity.
• Schedule #2 Once Weekly Dosing Schedule: Inability to administer both scheduled doses of PSMA ligand-tubulysin compound I in a cycle due to drug-related toxicity.
• PSMA imaging conjugate Ilia and PSMA ligand-tubulysin compound I was administered via IV bolus injection.
• PSMA-imaging conjugate Ilia 99m Tc-EC0652 showed good uptake in tumor lesions (See Figs. 1A and IB).

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• 2016
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